Acid Suppressive Pharmacology: PPIs, H2 Blockers, and Antacids Explained

Let's talk about acid suppressive pharmacology. We'll be talking about proton pump inhibitors, H2 blockers, and

a broad category called antacids. Proton pump inhibitors or PPIs are medications that end in prazole.

Omeprazole, pantoprazole, and more. Mechanistically, these medications irreversibly inhibit the HK ATPase,

which is found in gastric parietal cells. When you do this, you end up increasing the pH of the stomach, which

alleviates symptoms of things like GERD or peptic ulcer disease. Now, the benefit of PPIs is that there

is a high specificity for the environment that they function in. This is a brief aside that you don't

necessarily need to know for Step 1, but proton pump inhibitors are given in a chemically inactivated form. And the

chemically inactivated form becomes activated when it reaches an acidic environment. So, this is why the stomach

is essentially a highly specific environment in which PPIs function quite well.

Now, on your exam, if I had to guess, the test writer is going to go after the adverse effects and clinical

associations. Long-term use of PPIs is associated with a lot of different micronutrient

malabsorption problems. The big ones to be aware of on your exam are low levels of magnesium, vitamin B12, calcium, and

iron. So, your brain should start to think already that this is an opportunity for the test writer to give

you a question about a patient who might be taking PPIs. So, it may be a patient with GERD, it may be a patient with

peptic ulcer disease, but then the test writer can completely change course and connect that to something like a vitamin

B12 deficiency, which is a very clinically heterogeneous condition. So, the question starts with a patient who

has heartburn, and it's going to end with a question about vitamin B12. So, look for that connection because that's

how test writers like to think. Now, when it comes to long-term use, I mentioned you want to

think about low levels of magnesium, B12, calcium, and iron. Now, if you have somebody who can't absorb calcium and

magnesium, then what is the risk of long-term use? Increasing the risk of things like

osteoporosis. So, again, this is an opportunity for a test writer to start to write a question about a patient who

has chronic GERD, maybe long-standing peptic ulcer disease, and then they ask you, "Which of the following is the

patient at increased risk of in elderly age?" And the answer could either be fractures or osteoporosis.

Now, because the the gastric environment is becoming less acidic every time a patient takes a proton pump inhibitor,

the calcium that they would normally absorb remains bound to oxalate. So, it stays calcium oxalate. And when that

happens, the absorption of calcium is impaired because the duodenum and the jejunum relies on that acidic

environment to essentially separate calcium from oxalate. So, over the the long haul, as patients take these PPIs,

they have trouble absorbing calcium and magnesium, leading to increased risk of osteoporosis.

There are also some other associations. These are less high-yield, but know that there is an increased risk of pneumonia.

We're not exactly sure why that happens. We think it might have something to do with aspiration,

um an increased risk of interstitial nephritis, and increased risk of dementia, particularly and perhaps

obviously in individuals who are quite elderly. So, just know those associations. And

then lastly, there are certain proton pump inhibitors, esomeprazole and omeprazole, that have interactions with

other medications because they are enzyme CYP2C19 inhibitors. So, the medications on your

exam that you would want to look out for are things like warfarin, clopidogrel, and phenytoin. The bottom line here, if

I was writing the test question for a proton pump inhibitor, I would probably write a third-order question that starts

with a patient that is going to take a PPI. So, I'd give you sort of that classic GERD, peptic ulcer disease, GI

type patient, but then I would connect that in one into one of the malabsorption

uh clinical associations. And then the last thing, which I haven't mentioned thus far, but it is equally

important to know, is that in patients taking a proton pump inhibitor, there is an increased risk of a C. diff

infection. This issue is This warning is issued by the FDA. We're not exactly sure what is causing that association,

but it is definitely there. So, understand that in addition to everything else that I've mentioned, as

you can see on the slide, there's an increased risk of C. diff. Now, let's talk about H2 blockers. H2

blockers are medications like cimetidine, famotidine, etc. These agents will reversibly inhibit histamine

H2 receptors on the gastric parietal cells. Now, these histamine H2 receptors are G

protein-coupled receptors. And so, when you reversibly antagonize them, you decrease levels of adenylyl cyclase,

which decreases levels of cAMP, which decreases protein kinase A or PKA activity. And that ultimately leads to

decreased phosphorylation and therefore activation of the HK ATPase. And as we talked about with proton pump

inhibitors, when you decrease the HK ATPase, you decrease your levels of gastric acid secretion. So, you kind of

get to the same point that the PPIs get to. This just takes a little bit longer because you're going through the G

protein-coupled receptor pathway that hopefully you're comfortable with at this point if you've done a little bit

of biochem or immunology. Now, the clinical notes that you should know for the H2 blockers really just

have to do with cimetidine. Now, again, to be clear, cimetidine is not the only H2 blocker, right? There's famotidine,

there's nizatidine, um there's ranitidine, but cimetidine is the big one that has a lot of side effects. So,

as a test writer, if I was going to write you a question about an H2 blocker, I'm going to go after

cimetidine. The big one to know here is that cimetidine increases levels of prolactin. So, that is to say that in

men, this has an antiandrogenic effect. That can lead to things like erectile dysfunction, gynecomastia,

low libido, and so on your test, you're going to have a patient who has GERD, and then all of a sudden, they have

gynecomastia. And the test writer is going to ask you what was responsible for that. The answer could be

cimetidine. The answer could be increased release of prolactin, but you can see here that they're connecting two

seemingly unrelated topics and trying to trick you. Less high-yield, but still worth

knowing, is that cimetidine is also an inhibitor of cytochrome CYP2C19.

So, again, just like we talked about with the proton pump inhibitors, know your interactions with medications like,

for example, clopidogrel. And then this medication crosses the blood-brain barrier, so it can cause

things like altered mental status, confusion, headaches, dizziness. I should also point out, though it's not

mentioned on this slide, it can cross the placenta, um but is generally considered fairly safe.

Now, the mnemonic that I have is all having to do with cimetidine. So, cimetidine to me is C Met. C Met causes

C Men. And the C stands for C cups, which reminds me of gynecomastia, C for confusion, because again, it crosses the

blood-brain barrier and can can cause things like confusion and headache, and C19 inhibition. So, C Met for cimetidine

causes C Men. C cups for gynecomastia, and then, you know, take that one step further, it's generally just

antiandrogenic. Um so, things like erectile dysfunction, confusion, take that one step further,

headaches, blood-brain barrier, altered mental status, and C19 inhibition. Take that one step further, what medications

are metabolized by that enzyme, and etc. Also could have put C for crosses the the placenta. Um didn't put

it on this slide, but C Met for cimetidine does all the things starting with C.

And let's finally conclude with a broad category of medications known as antacids. So, these are things like

calcium carbonate, magnesium hydroxide, and aluminum hydroxide. Basically, this is the stuff that you keep in your

medicine cabinet to take when you get back from wing night as you get older. The mechanism here is that these

medications neutralize acid, so they lead to really quick symptom relief. And oftentimes, patients will utilize these

medications in addition to things like PPIs and H2 blockers. Now, the clinical notes here, there's a

couple things to point out, but this is really not a high-yield topic. All of these agents can cause hypokalemia. So,

I think that's probably the most important thing to know. All of these agents can also cause a lot of burping,

which can be kind of gross sometimes, and bloating. So, you want to be on the lookout for all of those symptoms, but

in particular, just focus on hypokalemia. Now, there are a few differences between

these different antacids, and I'll just point out a couple things. With calcium carbonate, it can cause something called

milk-alkali syndrome. Now, obviously, it has calcium in the name. So, calcium carbonate can increase levels of

calcium. But milk alkali syndrome is not necessarily a triad, but think of it as a triad as increased levels of

calcium, metabolic alkalosis, and an acute kidney injury. This can also act as a chelating agent for certain drugs.

And what that means is that a chelating agent essentially forms a complex with another medication. And so it'll bind to

metal ions and will lead to them being excreted. So you have to be careful when you give calcium carbonate around the

time that you give other medications. And for this reason, across this entire category, the recommendation is

generally to take antacids a few hours after or a few hours before taking other medications to avoid any type of

interaction. Getting back to other clinical associations, magnesium hydroxide can

cause things like diarrhea, hyporeflexia, and in rare instances cardiac arrest. And then aluminum

hydroxide can cause things like constipation, hypophosphatemia, and osteodystrophy.

This can cause other things that I have not put on this slide like muscle weakness,

muscle fatigue, and seizures. But broadly speaking, the most high-yield thing again to know is hypokalemia

across all of these agents. For calcium carbonate, I would know about milk alkali syndrome, so just increased

calcium, which is hopefully easy to remember because calcium is in the name, metabolic alkalosis, and acute kidney

injury. Mag hydroxide, diarrhea is the big one. Aluminum hydroxide, constipation is the big one. And those

are opposites, right? Magnesium hydroxide equals diarrhea. Aluminum hydroxide equals constipation. So if you

can keep this down, then antacid should just be a free point on test day. But that concludes this video on acid

suppressive agents. PPIs and H2 blockers are your big one, but antacids here for completeness. Good luck.